Process for the production of nitro phenyl amino diol derivatives



Patented Aug 17, 1954 UNITED STATES PATENT OFFICE PROCESS FOR THEPRODUCTION OF NITRO PHENYL AMINO DIrOL DERIVATIVES Allen 0. Moore,Grosse Pointe Woods, and George W. Moersch, Detroit, Mich., assignors toParke, Davis & Company, Detroit, Mich., a corporation of Michigan NoDrawing. Application December 12, 1950, Serial No. 200,488

This invention relates to a process for the production of nitrophenylamino diol derivatives. More particularly, the invention relates 12Claims. (Cl. 260-327) to a process for the production ofl-nitrophenylz-aminopropane-lfi-diol derivatives having the formula,

R1 on NH-R on-tnomon h-Form where R is hydrogen or an acyl radical andR1 is hydrogen, halogen, a lower alkyl or a lower alkoxy radical. Theterm acyl as used herein refers to carboxylic acid acyl radicals such aslower aliphatic acyl, halogenated lower aliphatic acyl, unsaturatedlower aliphatic acyl, ether substituted lower aliphatic acyl, benzoyl,halogenated benzoyl, nitrated benzoyl, alkylated benzoyl, araliphaticacyl and the like radicals.

From the following description it will be apparent to those skilled inthe art that both the starting materials and the products of the processexist in structural or diastero-isomeric as well as optical isomericform. The present invenconfiguration of thecompound. Where the notationHp-form appears, as it does above, the formula is to be interpreted inits generic sense, that is, as representing the (1) and (d) -41 isomersin separated form as well as the racemic mixture thereof. Such a formuladoes not merely represent the optically racemic mixture.

In accordance with the invention l-m'trophenyl 2 amino-propane 1,3 diolderivatives having the general formula given above are produced byreacting a l-phenyl-2-acylamidopropane-1,3-diol compound of formula,

yb-Form with a halide compound of formula,

to obtain a phenyl substituted cyclic compound of formula;

nitrating the phenyl ring of said cyclic compound to obtain anitrophenyl substituted cyclic compound of formula,

QJJH-cH-tm b-Form and hydrolyzing said nitrophenyl substituted cycliccompound; where R1 has the same ignificance as given above, X is ahalogen atom and Y is a -S0 or CO group.

Diagrammatically the process can be represented as follows:

i k-Form 3 lHNOa l l @cn-cn-cm NH-Acy1 N O 2 zy-Form Mild hydrolysisyb-Form l Hydrolysis V yb-Form where R1, X and Y have the samesignificance as given above.

The reaction between the halide compound and pseudo -1- phenyl -2-acylamidopropane-1,3- diol compound is carried out at a temperaturebelow 50 C. In the case of the thionyl halides, that is, whereY is SO,best results are obtained at a temperature between about 20 to 35 C.while the optimal temperature for the reaction with the carbonyl halidesis below about 20 C. and preferably at about to +10 C. The relativequantities of the reactants can be varied within rather wide limits.However, for economic reasons, as well as case of purification of theproducts, an excess of the halide compound is generally employed. In thecase of the thionyl halides one of the most convenient methods forcarrying' out the reaction involves the use of sufficient thionyl halideto act as a reaction medium or solvent. Other solvents which may be usedfor the reaction between the halide compound and the pseudo-lphenyl-2-acylarnidopropane-1,3-dio1 compound are inert, organic solventssuch as chloroform, methylene dichloride and the like. In the case ofthe carbonyl halides the preferred solvent for the reaction is atertiary organic amine such as'pyridine, N- ethylpiperidine,dimethylaniline, N-methylmorpholine, triethylamine and the like.

The reaction between the carbonyl halides, that is, where Y is CO, canalso be carried out under aqueous conditions. The preferred method is,however, to carry out the reaction under anhydrous conditions asdescribed above. In using aqueous conditions a two-phase reactionmixture is employed, that is, one phase consisting of one of theaforementioned inert organic solvents and the other consisting of watercontaining a weakly alkaline material such as calcium carbonate, calciumhydroxide, magnesium carbonate, sodium bicarbonate and the like to takeup the hydrogen halide formed. during the reaction.

The nitration of the phenyl ring of the phenyl substituted cycliccompound is carried out using fuming nitric acid, 100% nitric acid or amixture of concentrated nitric and sulfuric acids as the nitratingagent. The temperature during the reaction should be kept below about 10C. and preferably below l0 C.

' starting material and final product.

The nitrophenyl substituted cyclic compound obtained in th nitrationstep of the process can be converted by mild hydrolysis to thecorresponding pseudo 1 nitrophenyl 2 acylamidopropane-1,3-diol compound.This mild hydrolysis is carried out in a mixture composed of water and awater-miscible organic solvent such as methanol, ethanol, isopropanol,acetone, methyl ethyl ketone and the like using either an acidic oralkaline hydrolytic agent. As hydrolytic agents alkali metal hydroxidessuch as sodium hydroxide and potassium hydroxide, quaternary ammoniumhydroxides such as trimethylammonium hydroxide and triethylammoniumhydroxide and mineral acidssuch as hydrochloric acid, hydrobromic acidand sulfuric acid may be used. The temperature during the reaction isusually kept below about 50 C. although, if desired, the reactionmixture can be heated to boiling for a short time, such as ten minutesor less. Prolonged heating results in the conversion of the desiredpseudolnitrophenyl-2-acylamidopropane-1,3-diol compound into thecorresponding pseudo-l-nitrophenyl-2-aminopropane-l,3-diol compound andhence should be avoided. Generally speaking, the desired hydrolysisproceeds quite rapidly and is usually complete from within a few min- Iutes to one-half hour at temperatures between 20 and 50 C.

If desired, the nitrophenyl substituted cyclic compound obtained in thenitration step of the process can also be converted by hydrolysis to thecorresponding pseudo -1- nitrophenyl -2- aminopropane- 1,3 diolcompound. This is accomplished by heating the nitrophenyl substitutedcyclic compound for at least one hour with a dilute mineral acid. Bestresults are obtained by adding a water-miscible organic solvent to thereaction mixture-to increase the solubility of the The time required forthe hydrolysis varies with the nature of the acyl group on the aminonitrogen atom of the nitrophenyl substituted cyclic compound. Where theacyl group is on which is easily hydrolyzed such as an acetyl or adihaloacetyl group, the hydrolysis is usually complete at the end of theoneor two-hour heating period. However, Where the acyl group is onewhich is more resistant to hydrolysis such as a benzoyl or substitutedbenzoyl group a heating period of several hours is usually required.

The products obtained by the process of the present invention areantibiotics per se or are useful intermediates for the preparation ofother organic compounds possessing antibiotic activity.

The invention is illustrated by the following examples.

Example 1 SO 0 O (ill) -11/ Form 10 g. of the cyclic sulfite of(dZ)-.-1-phenyl- 2-dichloroacetamidopropane-1,3-diol is added in smallportions with stirring to. 50 cc. of 100% nitric acid cooled to about 30C. by the addition of solidicarbon dioxide. After the addition iscompleted, the reaction mixture is poured onto cracked ice and the whitesolid which separates collected. This product which is the cyclicsulfite of (dl) 1p 1 p nitrophenyl 2 dichloro-acetamidopropane 1,3 diolcan be purifled, if desired, by recrystallization from ethanol; M. P.1'75-6 C. Its formula is, I

(dB- Form Similar results are obtained by substituting fuming nitricacid or a mixture of concentrated.

nitric and sulfuric acids for the 100% nitric acid used in the aboveprocedure.

2 g. of the cyclic sulfite of (dZ)-1,b-1-p-nitrophenyl 2dichloroacetamidopropane 1,3 diol is dissolved in 50 cc. of warmethanol, 5 cc. of concentrated hydrochloric acid is added and themixture boiled for two or three minutes. The reaction mixture is cooled,neutralized with aqueous sodium hydroxide solution and evaporated on asteam bath to remove the ethanol. The aqueous residue is extracted withethyl acetate, the ethyl acetate distilled from the extracts and theresidue taken up in and recrystallized from water. The white crystallineproduct so obtained is (dl)0-1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol (M. P. 150 C.) offormula,

(dB-5b Form The hydrolysis of the cyclic sulfite of (dl) --1- pnitrophenyl 2 dichloroacetamidopropane- 1,3-diol can also be carried outas follows:

((0 3.7 g. of the cyclic sulfite of (dZ)-1, /-1-pnitrophenyl 2dichloroacetamidopropane- 1,3-diol is dissolved in 300 cc. of ethanol.225 cc. of 0.1 N sodium hydroxide solution is added and the mixtureallowed to stand at room temperature for one-half hour. The reactionmixture is neutralized with dilute hydrochloric acid and the ethanoldistilled in vacuo. The aqueous residue is extracted with ethyl acetate,the ethyl acetate extracts combined and the ethyl acetate distilledRecrystallization of the residue from ethylene dichloride yields thedesired (dl) --1-p-nitrophenyl 2 dichloroacetamidopropane 1,3 diol inpure form; M. P. 150-1 C.

(b) 2 g. of the cyclic sulfite of ((11) -;1/-1-p-nitrophenyl 2dichloroacetamidopropane 1,3 diol is dissolved in 65 cc. of ethanol. 5cc. of concentrated hydrochloric acid is added and the mixture allowedto stand at room temperature for twenty minutes. The reaction mixture isneutralized with 10% aqueous sodium hydroxide solution and the ethanoldistilled off in vacuo. The aqueous residue is extracted with ethylacetate, the extracts combined and the ethyl acetate distilled.Crystallization of the residue yields the desired(d1)-\//-1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol; M. P.150-1 C. I

. If desired, the cyclic sulfite of (dl) -I,0-1-p-nitrophenyl 2dichloroacetamidopropane 1,3 diol can be hydrolyzed to(dl)-i,bl-p-nitrophenyl-2- aminopropane-1,3-diol. plished as follows:

. 4 g. of the cyclic sulfite of (dl)--l-p-nitrophenyl 2dichloroacetamidopropane 1,3 diol is added to a mixture composed of cc.of ethanol and 150 cc. of 5% hydrochloric acid. The resulting mixture isheated under reflux for about two hours and then evaporated to drynessin This can be accomvacuo. The residual hydrochloride salt of (d1)- t 1p nitrophenyl 2 aminopropane 1,3-

diol is taken up in water, the solution :made alkaline with sodiumhydroxide and the precipitated product collected. The crude product isrecrystallizedfrom water to obtain the desired (all) -1//-1p-nitrophenyl-2-aminopropane-1,3-diol in pure form; M. P. 140.5" C. Theformula of this product is:

OH NH:

I I NOz-OCH-CH-OEDOH (all) 10 Form Example 2 (dl)x[/ Form 9 g. of thecyclic carbonate of (dl) --1-phenyl- 2-dichloroacetamidopropane-1,3-diolis added in small portions with stirring to 30 cc. of fuming nitric acidmaintained at 20 C. by the addition of small portions of solid carbondioxide. After the addition has been completed the reaction mixture ispoured onto ice and the white solid product collected. The solid isrecrystallized from ether and then from methanol to obtain the purecyclic carbonate of(all)--1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol. This productmelts poorly at -5 C. but analyzes correctly and upon mild hydrolysisgives a good yield of (dl) 1 p nitrophenyl 2dichloroacetamidopropane-1,3-diol. Its formula is:

O I NOrO-CH-CH-CH;

7. residual gum is dissolved in ethyl .acetate, the solution filteredand the ethyl acetateevaporated. Crystallization of the residual oilfrom water yields the desired(dl)--1-p-nitrophenyl#2-dichloroacetamidopropane-l,3-diol; M. P. :150"C. after recrystallization from ethylene dichloride. The formula ofthis product'is,

((11) a0 Form (om-1p Form in pure form; M. P. 140.25 C.

Example 3 g. of (Z) -1-phenyl-2:-dichloracetamidopropane-1,3-diol isadded in small portions with stirring to 30 cc. of thionyl chloride atroom temperature. The reaction mixture is allowed to stand at roomtemperature for about an hour and then ether added to precipitate thedesired cyclic sulfite of(Z)-\//-1-phenyl-2-dich1oroacetamidopropane-1,3-diol. The formula ofthis product is,

SO O O 9.5 g. of the cyclic sulfite of (Z) --1-phenyl-2dichloroacetamidopropane-1,3-diol is added in small portions withstirring to 50 .cc. of fuming nitric acid at 30 C. The temperatureduring the addition is maintained at about '20 C. by the addition ofsolid carbon dioxide. After the addition is completed, the reactionmixture is poured onto cracked ice and the white, solid cyclic sulfiteof (l)-\p- 1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-dio1collected. After recrystallization from ethanol the pure product meltsat 171-2" C. The formula of this product is,

phenyl-2-dichloroacetamidopropane 1,3 diol is dissolved in 125 cc. ofmethanol. 10 cc. of concentrated hydrochloric acid is added and themixture allowed to stand at room temperature for about twenty minutes.The reaction mixture is neutralized with 10% sodium hydroxide solutionand evaporated on a steam bath to remove the ethanol. The aqueousresidue is extracted with ethyl acetate, the ethyl acetate distilledfromthe combined extracts and the residue taken up in :and recrystallizedfrom ethyl acetate. The white crystalline product so obtained is (Z)-\,b-l-p-nitrophenyl 2 dichloroacetamidopropane-1,3-diol; M. P. -1 (7.;(oc) :25.5 in ethyl acetate. The formula of this product is,

(l)-1[/ Form 5 g. of the cyclic-sulfite of (l) --l-p-nitrophenyl-'2-dichloroacetamidopropane-1,3-diol solved in amixture composed of 150 cc.of ethanol and 150 cc. of 5% hydrochloric acid. The resulting mixture isheated under reflux for about two hours and then evaporated to drynessin vacuo. The residual hydrochloride salt of (Z) -1,bl-p-nitrophenyl-2aminopropane 1,3 diol is taken up in water, the solution made alkalinewith sodium hydroxide and the product collected. The insolubleprecipitate is recrystallized from water to obtain the desired (Z)-1p-l-p-nitro phenyl-2-aminopropane-1,3-dio1 in pure form; M. P. 162-30.; (a) =23 in methanol. The formula of this product is,

OH N112 (1)411 Form Example 4 15 g. of phosgene is added slowly over aperiod of three hours to 20 g. of(Z)-1,0-l-pheny1-2-dichloroacetamidopropane-1,3-diol dissolved in 50 cc.of dry pyridine. During the addition the temperature is kept in theneighborhood of 0 C. After the addition has been completed, the reactionmixture :is poured onto a large volume.

of ice and the White, cyclic carbonate of (Z) -l//-1-phenyl-2-dichloroacetamidopropane 1,3 diol collected and washed withWater. The formula of this product is,

15 g. of the cyclic carbonate of (Z) --l-phenyl-2-dichloroacetamidopropane-1,3-diol is added in small portions withstirring to 4 5 cc. of fuming nitric acid :and -20 -C. During theaddition the temperature is maintained at -20 C. by the addition ofsmall portions of solid carbon dioxide to the reaction mixture. Afterall of the cyclic carbonate has been added, the reaction mixture ispoured onto a large volume of ice. 'The insoluble white cyclic carbonateof (Z) -1-p-nitrophenyl-2-dichloroacetamidopropane 1,3 dlOlliScollected, washed with Water and recrystallized.

is dis- 9 from methanol; M. P. 157 C. The formula of this product is,

g. of the cyclic carbonate of (Z)-I//-1-nitrophenyl-2-dichloroacetamidopropane 1,3 diol is dissolved in75 cc. of ethanol. 3 cc. of concentrated hydrochloric acid is added andthe reaction mixture allowed to stand at room temperature for about tenminutes. The reaction mixture is neutralized with aqueous sodiumhydroxide solution, filtered and the filtrate evaporated to dryness invacuo. The residue is taken up in ethyl acetate, the solution filteredand the ethyl acetate removed by distillation. The residual oil iscrystallized from water to obtain the desired (Z) ill-1 p nitrophenyl 2dichloroacetamidopropane-1,3-diol; M. P. 150-1 C. afterrecrystallization from ethyl acetate; (06) =25.5 in ethyl acetate. Theformula of this product is,

(we Form 2 g. of the cyclic carbonate of (l) -\p-l-p-nitrophenyl 2dichloroacetamidopropane 1,3 diol is added to a mixture composed of 65cc. of ethanol and 75 cc. of 5%hydrochloric acid. The reaction mixtureis heated under reflux for two hours and then evaporated to dryness invacuo. The residue is taken up in water and made alkaline with sodiumhydroxide solution. The insoluble material is collected andrecrystallized from water to obtain the desired (2)--l-p-nitrophenyl-2-aminopropane-1,3-diol of formula,

(2H0 Form in pure form; M. P. 162-3 C.; (a) =23 in methanol.

Example 5 15 g. of (dl) b-1phenyl-Zbenzamidopropane- 1,3-diol is addedin small portions with stirring to cc. of trionyl chloride at roomtemperature. The reaction mixture is allowed to stand at roomtemperature for about an hour and then ether is added to precipitate thedesired cyclic sulfite of (dl) 1/1-lphenyl-2benzamidopropane 1,3 dial.The formula of this product is,

((11) Form 12 g. of the cyclicsulfite of (dD-Ip-l-pheny1-2-benzamidopropane-l,3-diol is added in small portions with stirring to 75cc. of fuming nitric acid at 20 C. The temperature during the additionis maintained in the neighborhood of 20" C. by the addition of solidcarbon dioxide. After the addition has been completed, the reactionmixture is poured onto a large volume of cracked iii ice and the whiteinsoluble cyclic sulfite of (all)- 11-1-1) nitrophenyl 2 mnitrobenzamidopropane-1,3-diol collected. The product is washed withwater and purified by recrystallization from ethanol. Its formula is, I

so 0 o J} N'Oz NOz-O-OHCH H, I I

(db-r0 Form 3 g. of the cyclic sulfite of (ill)-i,I/-1-p-nitrophenyl-Z-m'nitrobenzamidopropane 1,3 diol is dissolved inthe minimum amount of ethanol. 8 cc. of concentrated hydrochloric acidis added and the reaction mixture heatedat 35 C. for twenty minutes. Thereaction mixture is cooled, neutralized with aqueous sodium hydroxidesolution and the ethanol removed by distillation in vacuo. The insoluble;(dl) -1//-1-p'-nitrophenyl-2- mnitrobenzamidopropane-1,3-diol offormula,

(dB-301 mm is collected, washed with water and purified byrecrystallization from ethanol.

Example 6 10 g. of phosgene isadded slowly over a period of two hours to12 gjof (d1) d-l-phenyl-Z-acetamidopropane-l,3-diol in 65 cc. of drypyridine. During the addition thetemperature is maintained in theneighborhood of 5 C. Aiter the addition has been completed the reactionmixture is poured ontoice and the white solid cyclic carbonate of (dl) tl-phenyl-Z-acetamidopropane-1,3-dio1collected The product is washed withwater and dried. Its formula is,

(dl) Form 5 g. of the cyclic carbonate of (dl) -\//l-p-nitro-.phenyl-2acetamidopropane-1,3-diol is dissolved in '75 cc. of ethanol.2.5 cc. of concentrated hydrochloric acid is added and the mixtureallowed to stand at room temperature for-fifteen minutes. The reactionmixture is neutralized with sodium hydroxide solution, filtered and: thefiltrateevaporated to dryness-in vacuo. The residue is taken up in ethylacetate, the. solution filtered and the ethyl acetate distilled. Theresidual oil is crystallized from water'and' recrystallized from ethylacetate-petroleum ether mixture to obtain the desired (dZ)--1'-p-nitrophenyl 2 'acetamidopropane-1,3-dio1; M. P. 166-7 C. Theformula of this product is,

2 g. of the cyclic carbonate of (oil) -\,z/-1-pnitrophenyl 2acetamidopropane-1,3-dio1 is added to a mixture composed of 65' cc; ofethanol and 65 cc. of 5% sulfuric acid. The reaction mixture is heatedunder reflux for tWo hours and then the ethanol distilled from thereaction mixture. The solution is dilute-d with water and made alkalinewith sodium hydroxide solution. The insoluble material is taken up inethyl acetate, the ethyl acetate extracts dried and the ethyl acetatedistilled to; obtain the desired (d1)- 0-1-p-nitrophenyl-2-aminopropane1,3 diol;

(M. P. 140 C.). Its formula is,

OH IIIH: NOr--JJHCHCH2OH (dB-g0 Form Example 7 15 g. of(dl)-1-phenyl-2-acetamidopropane- 1,3-dio1 is added in small portionswith stirring to 35 cc. of thionyl chloride at room temperature, thereaction mixture allowed to stand at room temperature for one hour andthen diluted with ether to precipitate the desired cyclic sulfite of(dl)-1-\p-1-pheny1 2 acetamidopropane 1,3- diol. The formula-of thisproduct is,

l I OoH-oH-om (tin-1,0 Form 14.5 g. of the cyclic sulfite' of (111)--1-phenyl- Z-acetamidopropane-l,3-diol is added in small portions withstirring to 65 cc. of 100% nitric acid at -25 C. The temperature duringthe addition is maintained at about 20 C. by the addition of solidcarbon dioxide. After the addition has been completed, the reactionmixture is poured onto cracked ice and the white insoluble sulfite of(dl)--l-p-nitropheny1-Z-acetamidopropane-1,3-diol collected and purifiedby recrystallization from ethanol; M. P. 165-7 C. with decomposition.The. formulaof this product is,

| Nog in-( reon,

(dZHb'Fcrm 6 g. of the cyclic sulfite of(dl)-/-1-p-nitrophenyl-Z-acetamidopropanoe 1,3-dicl is dissolved in 125cc. of ethanol. 10 cc. of. concentrated (dB- ,0 Form 4 g. of the cyclicsulfite of (dl) --1-p-nitrophenyl-2-acetamidopropane-1,3-diol is addedto a mixture composed of cc. of ethanol and an equal volume of 5%hydrochloric acid. The resulting mixture is heated under reflux for twohours and then evaporated to dryness in vacuo. The residue is taken upin water, the solution made alkaline with sodium hydroxide and theinsoluble material recrystallized from water to obtain the desired(d2)-l//-l-p-nitrophenyl-2- aminopropane-1,3-diol (M. P. C.) of formula,

(db-5h Form Example 8 13 g. of (all) 0 1 (3-methoxyphenyl) -2-phenylacetamidopropane-l,3-diol is added in small portions with stirringto 30 cc. ofthionyl chloride at room temperature. The reaction mixtureis allowed to stand for one hour and then ether added to precipitate thedesired cyclic sulfite of ((11) p 1 (3-methoxyphenyl)--2-phenylacetamidopropane-1,3-diol of formula,

O (111)-1! Form 9.5 g. of cyclic sulfite of (oil) /-1- (3-methoxyphenyl)2 phenylacetamidopropane-l,3-diol is added in small portions withstirring to 50 cc. of 100% nitric acid at 20 C. The temperature duringthe addition is maintained at -20 C. by the addition of solid carbondioxide to the reaction mixture. After the addition has been completed,the reaction mixture is poured onto cracked ice and the white solidcyclic sulfite of (dl) 1p l-(3-methoxy 4 nitrophenyl) -2-pnitrophenylacetamidopropane-1,3-diol collected and purified byrecrystallization from ethanol. The formula of this product is,

N02 OCH:

(an-1p Form 5 g. of the cyclic sulfite of (all)--1-(3'-methoxy-Y-nitrophenyl) 2 p nitrophenylaceta- O CHs (db-P FormEzrample 9 15 g. of(d1)-1//-1-(2-methy1phenyl)-2-methoxy-aoetamidopropane-1,3-diol is addedin small portion with stirring to 40 cc. of thionyl chloride at roomtemperature. The reaction mixture is stirred for two hours and thendiluted with ether to precipitate the desired cyclic sulfite of (011)-1=(2-methylphenyl) 2 methoxyaoetamidopropane-1,3-diol of formula, j

(dB- ll Form 14 g. of the cyclic sulfite of (dl) --1-(2-methylphenyl) 2methoxyacetamidopropane 1,3- diol is added in small portions withstirring to '75 cc. of. 100% nitric acid at -30 C. The temperatureduring the addition is maintained at 30 C. by the addition of smallportions of solid carbon dioxide to the reaction mixture. After theaddition has been completed, the reaction mixture is poured onto crackedice and the white insoluble cyclic sulfite of (dl)-i[/-l- (2-methyl-4'-nitrophenyl)-2-methoxyacetamidopropane 1,3- diol collected, washed withwater and purified byrecrystallization from ethanol. The formula of thisproduct is,

.NOZ-QCH-on- Hz NH-C-CHzO CH3 (dB-511 Form l0 g. of the cyclic sulfiteof (dl) --1-(2'methyl-4-nitropheny1) 2-methoxyacetamidopropane- LB-diolis dissolved in 300 cc. of ethanol. 20 cc. of concentrated hydrochloricacid is added and the mixture allowed to stand at room temperature forabout twenty minutes. The reaction mixture is neutralized with 10%aqueous sodium hydroxide solution and the ethanol removed bydistillation in vacuo;

The aqueous residue is extracted with ethyl acetate, the ethyl acetatedistilled from the extracts and the residue taken up in and crystallizedfrom water. The crystalline product so obtained is recrystallized fromethyl acetate to obtain the desired (dl) -1p-l-(2"-methyl-4'nitrophenyl)-2-methoxyacetamidopropane- 14" 1,3-diol in pure form. The formula ofthis product is,

(db-c Form Example 10 used without further purification in the nextstep.

The formula of this compound is,

I Ortiz-( 11143112 (0-11 Form 15 g. of the cyclic carbonate of (l)--1-phenyl- 2-benzamidopropane-1,3-diol is added in small portions withstirring to 60 cc. of fuming nitric acid at 20 C. V The temperature ofthe reaction mixture is maintained at about 20 C. during the addition byadding small quantities of solid carbon dioxide. After all of the cycliccarbonate has been added, the reaction mixture is poured onto ice andthe insoluble cyclic carbonate of (Z) --1-p-nitrophenyl 2 mnitrobenzamidopropane-1,3-diol collected. The product is washed withwater and purified by recrystallization from methanol. The formula ofthis compound is,

/CO\ 0 o I N02 NOzOCH-(|JHGH2 i6 o (1H0 Form OH NHz I r NOrOEL-CH-OEBOH(l)- Form Example 11 16 g. of (dl) 4/ 1 (2'-chlorophen'yl) 2(ubromopropionamido)-propane-1,3-diol is added in small portions withstirring to 50 cc. of thionyl chloride at room temperature. After theaddition has been completed, the reaction mixture is allowed to stand atroom temperature for two hours and then diluted with ether toprecipitate the desired cyclic sulfite of (121) -1//-1-(2-chloro phenyl)-2- (a-bromopropionamido) propane-1,3- diol of formula,

(db-50 Form 8.5 g. of the cyclicsulfite of (dl) -1//-1-(2'-chlorophenyl) 2 (a bromopropionamido)propane- 1,3-diol' is added insmall portions with stirring to 50 cc. of 100% nitric acid at 25 C. Thetemperature during the addition is kept at about -25 C. by the additionof small quantities of solid carbon dioxide. After all of the cyclicsulfite has been addecLthe reaction mixture is poured onto cracked iceand the insoluble white cyclic sulfite of (all) -/l(2' chloro 5nitrophenyl)- 2 (a-bromopropionamido)propane-1,3-diol collected. Theproduct is washed with water and purified by recrystallization fromethanol. Its formula is,

so N02 l a F OOH-OH-CHz $1 l IH(fi-CHB1 CH:.

' (dB- ,0 Form 6 g. of the cyclic sulfite of (all) -/-1-(2'-chloro- 5nitrophenyl)-2=(ubromopropionamido) propane1,3-dio1 is dissolved inethanol. cc. of concentrated hydrochloric acid is added and the reactionmixture allowed to stand for about ten minutes. The reaction mixture isneutralized with 10% sodium hydroxide solution and the ethanol removedby distillation in vacuo. The aqueous residue is extracted with ethylacetate, the ethyl acetate distilled from the extracts and the residuestirred with water. "The insoluble material is collected and purified byrecrystallization from ethyl acetate. The product so obtained is(dZ)-\/-1-(2'-chloro 5' nitrophenyl)-2-(abromopropionamido) -propane 1,3diol of formula,

OH NH-R k-Form which comprises reacting a1-phenyl-2-acylamidopropanel,3-diol compound of formula,

with-a compound of the class consisting of thionyl '16 chloride andcarbonyl chloride to obtain a phenyl substituted cyclic compound offormula,

aaa. bIH-Acyl ip-Form reacting said phenyl substituted cyclic compoundwith a nitrating agent of the class consisting of fuming nitric acid,nitric acid and a mixture of concentrated nitric and sulfuric acids at atemperature below about 10 C. thereby nitrating the phenyl ring of saidcyclic compound to obtain a nitrophenyl substituted cyclic'compound offormula,

an es.

gD-Form and subjecting said nitrophenyl substituted cyclic compound tohydrolysis in a solvent composed of water and a water-miscible organicsolvent with a hydrolytic agent of the class consisting of alkali metalhydroxides, quaternary ammonium hydroxides and mineral acids; where R.is a member of the class consisting of hydrogen and carboxylic acid acylradicals, R1 is a member of the class consisting of hydrogen, halogen,lower alkyl and lower alkoxy radicals {.Y is a member of the classconsisting of SO-' and --CO- groups and X is a chlorine atom.

2. Process for the production of a l-nitrophenyl-2-acylamidopropane 1,3diol compound of formula,

R1 OH NH-Acyl r mcu-omon ill-Form which comprises reacting al-phenyl-Z-acylamidopropane-1,3-diol compound of formula,

R1 011 NH-Acyl \p-Form with a compound of the class consisting ofthionyl chloride and carbonyl chloride at a temperature below about 50C. to obtain a phenyl substituted cyclic compound of formula,

2 E -H-CH( 3H2 I IHAcy1 b-Form reacting said phenyl substituted cycliccompound with a nitrating agent of the class consisting of fuming nitricacid, 100% nitric acid and a. mix,- ture of concentrated nitric andsulfuric acids at a temperature below about 10 C. thereby nitrating thephenyl ring of said phenyl substituted cyclic compound to. form anitrophenyl substituted cyclic compound of formula,

and subjecting said nitrophenyl substituted cyclic compound to mildhydrolysis in a solvent composed of water and a water-miscible organicsol-,

vent by heating with a dilute mineral acid for less than minutes at atemperature above 50 0.; where R1 is amember of the class consisting ofhydrogen, halogen, lower alkyl and lower alkoxy radicals, Y is a memberof the class consisting of -SO- and --CO groups, acyl is carboxylic acidacyl and X is a chlorine atom.

3. Process for the production of l-nitrophenyl- 2-aminopropane-L3-diolcompound of formula,

which comprises reacting a I-phenyl-Z-acylamidopropane-1,3-diol compoundof formula,

R1 OH NH-Acyl I Suntan-ciao]:

, ll-Form with a halide compound of formula,

at a temperature below about 50 C'. to obtain a phenyl substitutedcyclic compound of formula,

NHAcyl ll-Form reacting said phenyl substituted cyclic compound with anitrating agent of the class consisting of fuming nitric acid, 100%nitric acidand a mixture of concentrated nitric and sulfuric acids at atemperature below about 10 Cathereby nitrating the phenyl ring of saidphenyl substituted cyclic compound to form a nitrophenyl substitutedcyclic compound of, formula,

and completely hydrolyzing said nitrophenyl substituted cyclic compoundby heating it with dilute mineral acid for at least one hour; where R1is a member of the class consisting of hydrogen, halogen, lower alkyland lower alkoxy radicals, Y is a member of the class consisting of SO--and -CO- groups, acyl is carboxylic acid acyl and X is a chlorine atom.

4. Process for the production of a l-p-nitrophenyl2-acylamidopropane-1,3-diol compound of formula,

which comprises reacting a 1-phenyl-2-acylamidopropane-1,3-diol compoundof formula,

OH NH-Acyl with thionyl chloride at a temperature between about 20 and35 C. to obtain a phenyl substituted cyclic sulfite compound of formula,

SO 0 O re na,

NH-Acyl D-Form reacting said phenyl substituted cyclic sulfite compoundwith a nitrating agent of the class consisting of fuming nitric acid,nitric acid and a mixture of concentrated nitric and sulfuric acids ata. temperature below about 10 C thereby nitrating the phenyl ring ofsaid phenyl substituted cyclic sulfite compound to form a nitrophenylsubstituted cyclic sulfite compound of formula,

l l NoOon-cn-om NH-Acyl b-Form and subjecting said nitrophenylsubstituted cyclic sulfite compound to mild hydrolysis in a solventmixture composed of water and a water-miscible organic solvent whereacyl is carboxylic acid acyl.

5. Process for the production of (Z) -\//l-pnitrophenyl 2dichloroacetamidopropane-1, 3- diol which comprises reacting (Z)-i//-1-pheny1-2- dichloroacetamidopropane-1,3-diol with thionyl chlorideat a temperature between about 20 and 35 C. to obtain the cyclic sulfiteof (Z) -ip-1- phenyl 2-diohloroacetamidopropane-1,3-diol of formula,

0 O r n,

(Z) all-Form reacting said cyclic sulfite with a ,nitrating agent of theclass consisting of fuming nitric acid, 100% nitric acid and a mixtureof concentrated nitric and sulfuric acids at a temperature below about10 C. thereby forming the cyclic sulfite of (Z) 1 pnitrophenyl-2-dichloroacetamidopropane- 1,3-diol of formula,

10" phenyl 2 dichloroacetamidopropane-1,3-diol of formula,

SO O (dbb Form reacting said cyclic sulfite with a nitrating agent ofthe class consisting of fuming nitric acid, 100% nitric acid and amixture of concentrated nitric and sulfuric acids at a temperature belowabout 10 C. thereby forming the cyclic sulfite of (all)- 0 1 pnitrophenyl Z-dichloroacetamidopropane-1,3-diol of formula,

NH(3-OHOlz (dB-1,0 Form and subjecting said cyclic sulfite of (dZ)/-1-pnitrophenyl 2 dichloroacetamidopropane-1,3- diol to mild hydrolysisin a solvent mixture composed of water and a water-miscible organicsolvent by heating with a dilute mineral acid for less than minutes at atemperature above 50 C.

'7. Process for the production of (dl) --1-pnitrophenyl 2aminopropane-l,3-diol which comprises reacting (rlZ) 1, 1phenyl-Z-acetamidopropane-Ld-diol with thionyl chloride at a temperaturebetween about 20 and 35 C. to obtain the cyclic white of (all)-i,'/-l-phenyl-2-acetamidopropane-1,3diol of formula,

SO 0 O NH-CCH3 (dl) 11 Form reacting said cyclic sulfite with anitrating agent of the class consisting of filming nitric acid, 100%nitric acid and a mixture of concentrated nitric and sulfuric acids at atemperature below about 10 C. thereby forming the cyclic sulfite of(all) 1/ 1 -'p nitrophenyl-Z-acetamidopropane-1,3- diol of formula,

(db- 0 Form and completely hydrolyzing said cyclic sulfite of ((12) 1,111 p-nitrophenyl-Z-acetamidopropane- 1,3-diol by heating it with dilutemineral acid for at least one hour.

8. Process for the production of a l-p-nitrophenyl2-acylamidopropane-1,3-diol compound of formula,

gb-Form which comprises reacting al-phenyl-2-acylamidopropane-1,3-dio1compound of formula,

OH NH-Acyl I QcH-oH-omoH Ix-Form with phosgene at a temperature betweenabout 10 and +10 C. in a tertiary organic amine to obtain a phenylsubstituted cyclic carbonate compound of formula,

NHAcyl l -Form reacting said phenyl substituted cyclic carbonatecompound with a nitrating agent of the class consisting of fuming nitricacid, nitric acid and a mixture of concentrated nitric and sulfuricacids at a temperature below about 10 C. thereby nitrating the phenylring of said phenyl substituted cyclic carbonate compound to form anitrophenyl substituted cyclic carbonate compound of formula,

NH-Acyl yh-Form and subjecting said nitrophenyl substituted cycliccarbonate compound to mild hydrolysis in a solvent mixture composed ofwater and a water-miscible organic solvent with a mineral acid at atemperature below 50 0., where acyl is carboxylic acid acyl.

9. Process for the production of (Z) -1//-1--p-nitrophenyl2-dichloroacetamidopropane-1,3-dio1 which comprises reacting (Z)-1//1-phenyl-2-dichloroacetamidopropane-1,3-diol with phosgene at atemperature between about -10 and +10 C. in a tertiary organic amine toobtain the cyclic carbonate of(l)-i//1-phenyl-2-dichloroacetamidopropane-1,3-diol of formula,

1,3-diol to mild hydrolysis in a solvent mixture composed of water and awater-miscible organic 21 solvent with a mineral acid at a temperaturebelow 50 C.

10. Process for the production of (dl) 11-1-11- nitrophenyl 2dichloroacetamidopropane-1,3- diol which comprises reacting(dl)--1-phenyl- 2-dichloroacetamidopropane-1,B-diol with phosgene at atemperature between about 10 and +10 C. in a tertiary organic amine toobtain the cyclic carbonate of (dl) -1p-1-phenyl-2-dichloroacetamidopropane-1,3-diol of formula,

(all) 10 Form and subjecting said cyclic carbonate of (dl) 11-1- pnitrophenyl 2 dichloroacetamidopropane- 1,3-diol to mild hydrolysis in asolvent mixture composed of water and a water-miscible organic solventwith a mineral acid at a temperature below 50 C.

11. Process which comprises reacting a heterocyclic compound of formula@om-oH-orn l lE-Acyl w-Form with a nitrating agent or the classconsisting or 22 fuming nitric acid, nitric acid and a mixture ofconcentrated nitric and sulfuric acids at a temperature below about 10C. thereby obtaining the corresponding nitro phenyl heterocycliccompound of formula NH-Acyl N02 ll-Form where R1 is a member of theclass consisting of hydrogen, halogen, lower alkyl and lower alkoxyradicals, Y is a member of the class consisting of SO-- and CO groups,acyl is carboxylic acid acyl and. X is a halogen atom.

12. Process which comprises reacting a compound having the formula 0/ \OOoH-( H-om NH-Acyl yll -Form with a nitrating agent of the classconsisting of fuming nitric acid, 100% nitric acid and a mixture ofconcentrated nitric and sulfuric acids at a temperature below about 10C. thereby obtaining the corresponding nitro phenyl heterocycliccompound of formula 0 o NoOon-bn-ona liTH-Acyl yhj-liorm where acyl iscarboxylic acid acyl.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,513,346 Moersch et a1 July 4, 1950 2,587,641 Moersch et a1Mar. 4, 1952

11. PROCESS WHICH COMPRISES REACTING A HETEROCYCLIC COMPOUND OF FORMULA12. PROCESS WHICH COMPRISES REACTING A COMPOUND OF FORMULA